O-linked pyrimidin-4-amine-based compounds, compositions comprising them, and methods of their use to treat cancer

Abstract

O-linked pyrimidin-4-amine-based compounds, pharmaceutical compositions comprising them, and methods of their use are described. Particular compounds of the invention are of formula I:

1. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 L 1  is a bond, —C(O)—, —SO 2 —, or —C(R 4 ) 2—;    
 L 2  is a bond, —O—, —C(O)—, —SO 2 —, —C(NOH)—, or —C(R 5 ) 2—;    
 A 2  is optionally substituted cycloalkyl, aryl or heterocycle; 
 R 1  is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl; 
 R 2  is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl; 
 each R 3  is independently ═O or optionally substituted lower alkyl; 
 each R 4  is independently hydrogen or lower alkyl; 
 each R 5  is independently hydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R 5  is hydroxyl, the other is neither hydroxyl nor fluoro; 
 each R 6  is halogen, —OH, —NH 2 , —NO 2 , —CN, or optionally substituted alkyl; 
 m is 0-4; and 
 p is 0-2. 
 
     
     
       2. The compound of  claim 1 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       3. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 L 1  is a bond, —C(O)—, —SO 2 —, or —C(R 4 ) 2 —; 
 L 2  is a bond, —O—, —C(O)—, —SO 2 —, —C(NOH)—, or —C(R 5 ) 2 —; 
 A 2  is optionally substituted cycloalkyl, aryl or heterocycle; 
 R 1  is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl; 
 R 2  is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl; 
 each R 3  is independently ═O or optionally substituted lower alkyl; 
 each R 4  is independently hydrogen or lower alkyl; 
 each R 5  is independently hydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R 5  is hydroxyl, the other is neither hydroxyl nor fluoro; 
 each R 6  is halogen, —OH, —NH 2 , —NO 2 , —CN, or optionally substituted alkyl; 
 m is 0-4; and 
 q is 0-4. 
 
     
     
       4. The compound of  claim 1  or  3 , wherein A 2  is optionally substituted phenyl, pyridine, quinoline, thiophene, indole, pyrazole, piperidine, morpholine, or pyrrolidine. 
     
     
       5. The compound of  claim 1  or  3 , wherein L 2  is —O—. 
     
     
       6. The compound of  claim 1  or  3 , wherein L 2  is —C(O)— or —C(NOH)—. 
     
     
       7. The compound of  claim 1  or  3 , wherein L 2  is —C(R 5 ) 2 —. 
     
     
       8. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 L 2  is a bond, —O—, —C(O)—, —SO 2 —, —C(NOH)—, or —C(R 5 ) 2 —; 
 A 1  is optionally substituted cycloalkyl, aryl or heterocycle; 
 R 1  is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl; 
 R 2  is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl; 
 each R 3  is independently ═O or optionally substituted lower alkyl; 
 each R 4  is independently hydrogen or lower alkyl; 
 each R 5  is independently hydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R 5  is hydroxyl, the other is neither hydroxyl nor fluoro; 
 each R 7  is halogen, —OR 8 , —NH 2 , —NO 2 , —C(O)N(R 8 ) 2 , —CN, or optionally substituted alkyl, aryl or heterocycle; 
 each R 8  is hydrogen or optionally substituted alkyl; 
 n is 1-3; 
 m is 0-3 if n is 1, m is 0-4 if n is 2, or m is 0-5 if n is 3; and 
 r is 0-5. 
 
     
     
       9. The compound of  claim 8 , wherein A 1  is optionally substituted imidazole, pyridine, pyrimidine, purine, triazine, or thiazole. 
     
     
       10. The compound of  claim 8 , wherein R 7  is —OR 8 , C(O)N(R 8 ) 2 , or —CN. 
     
     
       11. The compound of  claim 8 , wherein R 7  is an optionally substituted non-aromatic heterocycle. 
     
     
       12. The compound of  claim 11 , wherein the heterocycle is hexahydropyrimidine, morpholine, piperidine, pyrrolidine, or 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidine. 
     
     
       13. The compound of  claim 8 , wherein L 2  is —O—. 
     
     
       14. The compound of  claim 8 , wherein L 2  is —C(O)— or —C(NOH)—. 
     
     
       15. The compound of  claim 8 , wherein L 2  is —C(R 5 ) 2 —. 
     
     
       16. The compound of  claim 8 , wherein R 1  is halogen. 
     
     
       17. The compound of  claim 8 , wherein R 2  is hydrogen. 
     
     
       18. A composition comprising a compound of  claim 1 ,  3 , or  8  and a pharmaceutically acceptable excipient or diluent.